The Ionasphere

NEUROTHEOLOGY 101 ATTACHMENTS, Cont.

In 1995, to an audience of 6,000
scientists, V.S. Ramachandran (known to friends and colleagues as "Rama")
delivered the inaugural "Decade of the Brain" lecture at the Silver Jubilee
meeting of the Society for Neuroscience, this country's leading organization
for brain research. His talk, laced with wit and humor, received a standing
ovation. Ramachandran also delivered the "Decade of the Brain" lecture
to the Library of congress and the NIH. Her received invitations to give
The Dorcus Cumming Plenary Lecture at Cold Spring Harbor, and the Weissman
Memorial Lecture at the Weissman Institute, Israel. He is in great demand
as a speaker, both for scientific and lay audiences.

Rama is on the editorial boards
of several international journals and has published over 110 scientific
papers, including three invited review articles for Scientific American.
He edited a four volume Encyclopedia of Human Behavior that was
cited by Library Journal as "the most outstanding reference for 1994 in
the behavioral sciences." In 1995 he was elected a member of the Atheneum,
the world's oldest scientific club, founded in London by Michael Faraday
and Humphrey Davy . He has appeared on numerous television programs (PBS,
BBC, German television) and his work has been featured in The New York
Times, Discover, National Geographic, Time and Life.

Originally trained as a physician
at Stanley Medical College, where he was awarded gold medals in pathology
and clinical medicine,Ramachandran went on to earn a PhD in neurology from
Trinity College at Cambridge University. Before moving to La Jolla, he
held appointments at Oxford University and the California Institute of
Technology. In 1998 he received a Gold medal from the Australian national
university and in "99 the Ariens Kappers Medal by the Royal Netherlands
Academy of Sciences for landmark achievements in neurosciences. In the
same year he was elected a fellow of All Souls College Oxford. and Newsweek
named him a member of the "Century Club" — one of hundred people to watch
as America enters the next century. Today he works exclusively with human
neurological patients and one of his main interests is in the neurological
basis of art. He has been lecturing widely on this subject not only to
scientists, but to art galleries and museums.

— JB

V.S.
RAMACHANDRAN is professor of Neuroscience and Psychology
and Director of Center for Brain and Cognition at the University of California
at San Diego. He also holds joint appointments at the Salk Institute in
La Jolla and with the Cognitive Sciences Program at UCSD. He is also a
physician. A dynamic speaker who rolls his r's and flourishes vowels, Dr.
Ramachandran gives scientific talks the world over. His book Phantoms
In The Brain (with Sandra Blakeslee) was selected as one of the best
books of 1998 by
The Economist and was a finalist for the Los
Angeles Times Book Prize. It was on the "Editors Choice" list in Scientific
American, Discover Magazine and The American Scientist.

*
* *

The discovery of mirror neurons
in the frontal lobes of monkeys, and their potential relevance to human
brain evolution — which I speculate on in this essay — is the single most
important "unreported" (or at least, unpublicized) story of the decade.
I predict that mirror neurons will do for psychology what DNA did for biology:
they will provide a unifying framework and help explain a host of mental
abilities that have hitherto remained mysterious and inaccessible to experiments.

There are many puzzling questions
about the evolution of the human mind and brain:

1) The hominid brain reached
almost its present size — and perhaps even its present intellectual capacity
about 250,000 years ago . Yet many of the attributes we regard as uniquely
human appeared only much later. Why? What was the brain doing during the
long "incubation "period? Why did it have all this latent potential for
tool use, fire, art music and perhaps even language- that blossomed only
considerably later? How did these latent abilities emerge, given that natural
selection can only select expressed abilities, not latent ones? I shall
call this "Wallace's problem", after the Victorian naturalist Alfred Russell
Wallace who first proposed it.

2) Crude "Oldawan" tools — made
by just a few blows to a core stone to create an irregular edge — emerged
2.4 million ago and were probably made by Homo Habilis whose brain size
was half way (700cc) between modern humans (1300) and chimps (400). After
another million years of evolutionary stasis aesthetically pleasing "symmetrical"
tools began to appear associated with a standardization of production technique
and artifact form. These required switching from a hard hammer to a soft
(wooden?) hammer while the tool was being made, in order to ensure a smooth
rather than jagged, irregular edge. And lastly, the invention of stereotyped
"assembly line" tools (sophisticated symmetrical bifacial tools) that were
hafted to a handle, took place only 200,000 years ago. Why was the evolution
of the human mind "punctuated" by these relatively sudden upheavals of
technological change?

3) Why the sudden explosion
(often called the "great leap" ) in technological sophistication, widespread
cave art, clothes, stereotyped dwellings, etc. around 40 thousand years
ago, even though the brain had achieved its present "modern" size almost
a million years earlier?

4) Did language appear completely
out of the blue as suggested by Chomsky? Or did it evolve from a more primitive
gestural language that was already in place?

5) Humans are often called the
"Machiavellian Primate" referring to our ability to "read minds" in order
to predict other peoples' behavior and outsmart them. Why are apes and
humans so good at reading other individuals' intentions? Do higher primates
have a specialized brain center or module for generating a "theory of other
minds" as proposed by Nick Humphrey and Simon Baron-Cohen? If so, where
is this circuit and how and when did it evolve?

The solution to many of these
riddles comes from an unlikely source.. the study of single neurons in
the brains of monkeys. I suggest that the questions become less puzzling
when you consider Giaccamo Rizzollati's recent discovery of "mirror neurons'
in the ventral premotor area of monkeys. This cluster of neurons, I argue,
holds the key to understanding many enigmatic aspects of human evolution.
Rizzollati and Arbib have already pointed out the relevance of their discovery
to language evolution . But I believe the significance of their
findings for understanding other equally important aspects of human evolution
has been largely overlooked. This, in my view, is the most important unreported
"story" in the last decade.

THE EMERGENCE OF LANGUAGE

Unlike many other human traits
such as humor, art, dancing or music the survival value of language is
obvious — it helps us communicate our thoughts and intentions. But the
question of how such an extraordinary ability might have actually evolved
has puzzled biologists, psychologists and philosophers at least since the
time of Charles Darwin. The problem is that the human vocal apparatus is
vastly more sophisticated than that of any ape but without the correspondingly
sophisticated language areas in the brain the vocal equipment alone would
be useless. So how did these two mechanisms with so many sophisticated
interlocking parts evolve in tandem? Following Darwin's lead I suggest
that our vocal equipment and our remarkable ability to modulate voice evolved
mainly for producing emotional calls and musical sounds during courtship
("croonin a toon."). Once that evolved then the brain — especially the
left hemisphere — could evolve language.

But a bigger puzzle remains.
Is language mediated by a sophisticated and highly specialized "language
organ" that is unique to humans and emerged completely out of the blue
as suggested by Chomsky? Or was there a more primitive gestural communication
system already in place that provided a scaffolding for the emergence of
vocal language?

Rizzolatti's discovery can help
us solve this age-old puzzle. He recorded from the ventral premotor area
of the frontal lobes of monkeys and found that certain cells will fire
when a monkey performs a single, highly specific action with its hand:
pulling, pushing, tugging, grasping, picking up and putting a peanut in
the mouth etc. different neurons fire in response to different actions.
One might be tempted to think that these are motor "command" neurons, making
muscles do certain things; however, the astonishing truth is that any given
mirror neuron will also fire when the monkey in question observes another
monkey (or even the experimenter) performing the same action, e.g. tasting
a peanut!

With knowledge of these neurons,
you have the basis for understanding a host of very enigmatic aspects of
the human mind: "mind reading" empathy, imitation learning, and even the
evolution of language. Anytime you watch someone else doing something (or
even starting to do something), the corresponding mirror neuron might fire
in your brain, thereby allowing you to "read" and understand another's
intentions, and thus to develop a sophisticated "theory of other minds."
(I suggest, also, that a loss of these mirror neurons may explain autism
— a cruel disease that afflicts children. Without these neurons the child
can no longer understand or empathize with other people emotionally and
therefore completely withdraws from the world socially.)

Mirror neurons can also enable
you to imitate the movements of others thereby setting the stage for the
complex Lamarckian or cultural inheritance that characterizes our species
and liberates us from the constraints of a purely gene based evolution.
Moreover, as Rizzolati has noted, these neurons may also enable you to
mime — and possibly understand — the lip and tongue movements of others
which, in turn, could provide the opportunity for language to evolve. (This
is why, when you stick your tongue out at a new born baby it will reciprocate!
How ironic and poignant that this little gesture encapsulates a half a
million years of primate brain evolution.) Once you have these two abilities
in place the ability to read someone's intentions and the ability to mime
their vocalizations then you have set in motion the evolution of language.
You need no longer speak of a unique language organ and the problem doesn't
seem quite so mysterious any more.

(Another important piece of
the puzzle is Rizzolatti's observation that the ventral premotor area may
be a homologue of the "Broca's area" — a brain center associated with the
expressive and syntactic aspects of language in humans).

These arguments do not in any
way negate the idea that there are specialized brain areas for language
in humans. We are dealing, here, with the question of how such areas may
have evolved, not whether they exist or not.

Mirror neurons were discovered
in monkeys but how do we know they exist in the human brain? To find out
we studied patients with a strange disorder called anosognosia. Most patients
with a right hemisphere stroke have complete paralysis of the left side
of their body and will complain about it, as expected. But about 5% of
them will vehemently deny their paralysis even though they are mentally
otherwise lucid and intelligent. This is the so called "denial" syndrome
or anosognosia.

To our amazement, we found that
some of these patients not only denied their own paralysis, but also denied
the paralysis of another patient whose inability to move his arm was clearly
visible to them and to others. Denying ones one paralysis is odd enough
but why would a patient deny another patient's paralysis? We suggest that
this bizarre observation is best understood in terms of damage to Rizzolatti's
mirror neurons. It's as if anytime you want to make a judgement about someone
else's movements you have to run a VR (virtual reality) simulation of the
corresponding movements in your own brain and without mirror neurons you
cannot do this .

The second piece of evidence
comes from studying brain waves (EEG) in humans. When people move their
hands a brain wave called the MU wave gets blocked and disappears completely.
Eric Altschuller, Jamie Pineda, and I suggested at the Society for Neurosciences
in 1998 that this suppression was caused by Rizzolati's mirror neuron system.
Consistent with this theory we found that such a suppression also occurs
when a person watches someone else moving his hand but not if he watches
a similar movement by an inanimate object. (We predict that children with
autism should show suppression if they move their own hands but not if
they watch some one else. Our lab now has preliminary hints from one highly
functioning autistic child that this might be true (Social Neuroscience
Abstracts 2000).

THE BIG BANG OF HUMAN EVOLUTION

The hominid brain grew at an
accelerating pace until it reached its present size of 1500cc about 200,000
years ago. Yet uniquely human abilities such the invention of highly sophisticated
"standardized" multi- part tools, tailored clothes, art, religious belief
and perhaps even language are thought to have emerged quite rapidly around
40,000 years ago — a sudden explosion of human mental abilities and culture
that is sometimes called the "big bang." If the brain reached its full
human potential — or at least size — 200,000 years ago why did it remain
idle for 150,000 years?

Most scholars are convinced
that the big bang occurred because of some unknown genetic change in brain
structure. For instance, the archeologist Steve Mithen has just written
a book in which he claims that before the big bang there were three different
brain modules in the human brain that were specialized for "social or machiavellian
intelligence", for "mechanical intelligence" or tool use, and for "natural
history" (a propensity to classify). These three modules remained isolated
from each other but around 50,000 years ago some genetic change in the
brain suddenly allowed them to communicate with each other, resulting in
the enormous flexibility and versatility of human consciousness.

I disagree with Mithen ingenious
suggestion and offer a very different solution to the problem. (This is
not incompatible with Mithen's view but its a different idea). I suggest
that the so-called big bang occurred because certain critical environmental
triggers acted on a brain that had already become big for some other
reason and was therefore "pre-adapted" for those cultural innovations that
make us uniquely human. (One of the key pre adaptations being mirror neurons.)

Inventions like tool use, art,
math and even aspects of language may have been invented "accidentally"
in one place and then spread very quickly given the human brain's amazing
capacity for imitation learning and mind reading using mirror neurons.
Perhaps ANY major "innovation" happens because of a fortuitous coincidence
of environmental circumstances — usually at a single place and time. But
given our species' remarkable propensity for miming, such an invention
would tend to spread very quickly through the population — once it emerged.

Mirror neurons obviously cannot
be the only answer to all these riddles of evolution. After all
rhesus monkeys and apes have them, yet they lack the cultural sophistication
of humans (although it has recently been shown that chimps at least DO
have the rudiments of culture, even in the wild). I would argue, though,
that mirror neurons are Necessary but not sufficient: their emergence
and further development in hominids was a decisive step. The reason is
that once you have a certain minimum amount of "imitation learning" and
"culture" in place, this culture can, in turn, exert the selection pressure
for developing those additional mental traits that make us human . And
once this starts happening you have set in motion the auto-catalytic process
that culminated in modern human consciousness.

A second problem with my suggestion
is that it doesn't explain why the many human innovations that constitute
the big bang occurred during a relatively short period. If its simply a
matter of chance discoveries spreading rapidly,why would all of them have
occurred at the same time? There are three answers to this objection. First,the
evidence that it all took place at the same time is tenuous. The invention
of music, shelters,hafted tools, tailored clothing, writing, speech, etc.
may have been spread out between 100K and 5k and the so-called great leap
may be a sampling artifact of archeological excavation. Second, any given
innovation (e.g. speech or writing or tools) may have served as a catalyst
for the others and may have therefore accelerated the pace of culture as
a whole. And third, there may indeed have been a genetic change,b ut it
may not have been an increase in the ability to innovate ( nor a breakdown
of barriers between modules as suggested by Mithen) but an increase in
the sophistication of the mirror neuron system and therefore in "learnability."

The resulting increase in ability
to imitate and learn (and teach) would then explain the explosion of cultural
change that we call the "great leap forward" or the "big bang" in human
evolution. This argument implies that the whole "nature-nurture debate"
is largely meaningless as far as human are concerned. Without the genetically
specified learnability that characterizes the human brain Homo sapiens
wouldn't deserve the title "sapiens" (wise) but without being immersed
in a culture that can take advantage of this learnability, the title would
be equally inappropriate. In this sense human culture and human brain have
co-evolved into obligatory mutual parasites — without either the result
would not be a human being. (No more than you can have a cell without its
parasitic mitochondria).

THE SECOND BIG BANG

My suggestion that these neurons
provided the initial impetus for "runaway" brain/ culture co-evolution
in humans, isn't quite as bizarre as it sounds. Imagine a martian anthropologist
was studying human evolution a million years from now. He would be puzzled
(like Wallace was) by the relatively sudden emergence of certain mental
traits like sophisticated tool use, use of fire, art and "culture" and
would try to correlate them (as many anthropologists now do) with purported
changes in brain size and anatomy caused by mutations. But unlike them
he would also be puzzled by the enormous upheavals and changes that occurred
after (say) 19th century — what we call the scientific/industrial revolution.
This revolution is, in many ways, much more dramatic (e.g. the sudden emergence
of nuclear power, automobiles, air travel, and space travel) than the "great
leap forward" that happened 40,000 years ago!!

He might be tempted to argue
that there must have been a genetic change and corresponding change
in brain anatomy and behavior to account for this second leap forward.
(Just as many anthropologists today seek a genetic explanation for the
first one.) Yet we know that present one occurred exclusively because
of fortuitous environmental circumstances, because Galileo invented
the "experimental method," that, together with royal patronage and the
invention of the printing press, kicked off the scientific revolution.
His experiments and the earlier invention of a sophisticated new language
called mathematics in India in the first millennium AD (based on place
value notation, zero and the decimal system), set the stage for Newtonian
mechanics and the calculus and "the rest is history" as we say.

Now the thing to bear in mind
is that none of this need have happened. It certainly did not happen
because of a genetic change in the human brains during the renaissance.
It happened at least partly because of imitation learning and rapid "cultural"
transmission of knowledge. (Indeed one could almost argue that there was
a greater behavioral/cognitive difference between pre-18th century
and post 20th century humans than between Homo Erectus and archaic Homo
Sapiens. Unless he knew better our Martian ethologist may conclude that
there was a bigger genetic difference between the first two groups than
the latter two species!)

Based on this analogy I suggest,
further, that even the first great leap forward was made possible
largely by imitation and emulation. Wallace's question was perfectly sensible;
it is very puzzling how a set of extraordinary abilities seemed
to emerge "out of the blue". But his solution was wrong...the apparently
sudden emergence of things like art or sophisticated tools was not because
of God or "divine intervention". I would argue instead that just as a single
invention (or two) by Galileo and Gutenberg quickly spread and transformed
the surface of the globe (although there was no preceding genetic
change), inventions like fire, tailored clothes, "symmetrical tools", and
art, etc. may have fortuitously emerged in a single place and then
spread very quickly.

Such inventions may have been
made by earlier hominids too (even chimps and orangs are remarkably inventive...who
knows how inventive Homo Erectus or Neandertals were) but early hominids
simply may not have had an advanced enough mirror neuron system to allow
a rapid transmission and dissemination of ideas. So the ideas quickly drop
out of the "meme pool". This system of cells, once it became sophisticated
enough to be harnessed for "training" in tool use and for reading other
hominids minds, may have played the same pivotal role in the emergence
of human consciousness (and replacement of Neandertals by Homo Sapiens)
as the asteroid impact did in the triumph of mammals over reptiles.

So it makes no more sense to
ask "Why did sophisticated tool use and art emerge only 40,000 years ago
even though the brain had all the required latent ability 100,000
years earlier?" — than to ask "Why did space travel occur only a few decades
ago, even though our brains were preadapted for space travel at least as
far back Cro Magnons?". The question ignores the important role of contingency
or plain old luck in human evolutionary history.

Thus I regard Rizzolati's discovery
— and my purely speculative conjectures on their key role in our evolution
— as the most important unreported story of the last decade.

SANTA FE, N.M. — Physicists observe the natural world and extract from
it laws and principles that reliably explain everyday phenomena. At the
smallest scale, they use quantum mechanics to predict the behavior of subatomic
particles and small molecules. At larger scales, they devise theories to
explain magnetism, the conduction of heat and electricity and other phenomena
that occur the same way in a wide variety of materials.

Scientists boast that these principles predict how most matter will behave
in physical and chemical experiments.

But there is one region that eludes them. That is the region containing
matter on a scale of 10 to 1,000 angstroms (an angstrom being one ten-billionth
of a meter) — bigger than a simple molecule but smaller than a living cell.
This is the realm in which the constituents of cells interact with one
another.

It is where proteins fold, charged ions move through cell membranes and
messenger molecules read DNA instructions in the cell nucleus. Even the
most advanced microscopes can only glimpse this activity, because the energies
they use tend to destroy living tissue, said Dr. David Pines, a physicist
at the Los Alamos National Laboratory.

At this level, things do not act according to well-described theories of
chemistry and physics. Rather, systems this size seem to obey a unique
set of rules that cannot be deduced from studying their individual components.

There are too many atoms in the systems to be described by electromagnetism
and quantum theories but too few to handle statistically.

This is the realm of "the mesoscale," and scientists like Dr. Pines and
Dr. Robert Laughlin, the Nobel laureate from Stanford, are attacking its
mysteries.

"I think we'll see some answers, but it will take a generation or two,"
Dr. Laughlin said in a recent interview. "It won't happen tomorrow."

Work has begun under the auspices of the Institute for Complex Adaptive
Matter or ICAM, a new and independent unit of the Los Alamos National Laboratory
and the University of California at Berkeley, which administers the lab.
Led by Dr. Pines and Dr. Laughlin, the physicists, chemists and biologists
of ICAM met here this year to discuss how scientists might try to understand
and maybe even design matter that organizes itself into living systems.

Unlike the Santa Fe Institute and other centers that study complexity,
ICAM scientists tend to shun computer models and the jargon of complex
systems. Nor do they have much faith in efforts to understand life by sequencing
genes and looking for similar patterns in different organisms.

Without deeper organizing principles, they say, the mere accumulation and
organization of genetic data will not shed light on how life works.

Research on the mesoscale must be based on experiments, Dr. Laughlin said.
"It's about making stuff, putting matter into new situations so you may
discover something new. Then you do your best to disprove your theory.
Physics teaches us that rules dreamt up without the benefit of physical
insight are nearly always wrong. Correct rules must be discovered, not
invented."

As an example, he cites 19th century physicists who believed light needed
some kind of medium, called ether, to spread through the universe. But
this wholly fabricated invention was overturned when Albert Einstein accepted
at face value experiments that found light travels at a constant speed
and "went on to make his astonishing predictions about the dilation of
time and the equivalence of mass and energy, both of which have now been
verified in countless experiments," Dr. Laughlin said.

Nanotechnology is exploring matter at the mesoscale and holds promise for
discovering new principles, Dr. Laughlin said. But until it develops some
theories, it will not be able to test new ideas about how living systems
are organized. Mathematicians are beginning to make important contributions
that help model and understand biological systems, he said, but laboratory
experiments still need to guide their thinking.

To start with, ICAM researchers are focusing on one beguiling fact: complex
systems can arise out of simple constituents that interact with each other
in ways not necessarily obvious.

In Dr. Laughlin's view, life is constructed according to engineering principles
or laws that do not change, though they are observed at different scales
under different conditions, Dr. Laughlin said. For example, the laws of
hydrodynamics — the science that deals with the motions of fluids and the
forces acting on solid bodies immersed in fluids — are the same in a wide
variety of materials. Do these so-called "protected" laws exist at the
mesoscale? No one attending the ICAM meeting claimed to have the answer.
But they discussed a variety of ways to find out.

One approach involves studying the way small molecules called amino acids
fold themselves up to make functional proteins. When a gene directs messenger
RNA to make a protein, it activates machinery that produces a linear chain
of amino acids that code for the protein. Scientists used to think that
the same linear sequence of amino acids always led to the same protein,
said Dr. Peter Wolynes, a chemist at the University of California at San
Diego. They also thought that proteins followed more or less the same course
when they folded.

But now, Dr. Wolynes said, scientists know that a huge variety of amino
acid sequences can fold up to form the same protein. Moreover, the same
string of amino acids fol ded differently creates a protein that acts differently
in the body. These findings have turned protein folding into one of the
most intractable problems in biology. For example, a big protein like myoglobin,
the iron-bearing pigment in muscles, can be made by any one of many millions
of different amino acid sequences.

What makes a protein follow one of these many folding possibilities to
achieve its functional shape? The answer, Dr. Wolynes said, lies in what
he and other researchers call "funnels" in the multidimensional landscape
of folding possibilities. Like real funnels that force material to flow
in one direction, protein funnels are produced when amino acids try many
different configurations and are drawn by an interplay of positive and
negative forces to flow or fold in one direction.

But the detailed physical interactions that may create these funnels are
not well understood.

Dr. James Shapiro, a professor of microbiology at the University of Chicago
and an ICAM researcher, said that interactions among components in a system
were the keys to understanding the emergence of complex systems.

These interactions include dynamic properties like feedback and checkpoints,
at which the system checks to make sure everything is all right, which
are seen everywhere in living cells, he said. All kinds of signals inform
cells where they are at a given time, where their neighbors are, what they
are supposed to do next and how and when to stop, Dr. Shapiro said.

Feedback and control are processes that lead to protected states in the
mesoscale, which need to be explored experimentally. Dr. M. Reza Ghadiri,
a chemist at the Scripps Research Institute in San Diego has in his laboratory
created small systems of organic molecules that faithfully make copies
of themselves and use feedback to change their dynamics.

These molecular ecosystems are not life, he said, but they do show emergent
properties like the ability to reproduce, form parasites, correct errors
and engage in symbiosis.

Dr. Laughlin challenged biologists to double-check some of their classic
experiments used to explain how DNA works at a molecular level. For example,
many details of accepted theories of how DNA actually makes proteins are
"appallingly bad," he said.

"I've just written a paper on this subject, which is considered nutty by
many experts and visionary by others," he said. He said it would be published
soon in The Proceedings of the National Academy of Sciences and added that
he welcomed vigorous debate about it.

At Harvard, Dr. George Whitesides is experimenting with magnetite and iron
beads to explore how forces of repulsion, attraction and energy dissipation
interact to form unpredictable complex patterns. As these simple systems
evolve, Dr. Whitesides said, it should be possible to explore the dynamics
of interacting particles and perhaps model biological principles.

"We are letting nature tell us what it likes to do," he said. Such experiments
have extraordinary implications, Dr. Pines said. Unlike vitalism — a doctrine
that says the processes of life are not explicable by the laws of physics
and chemistry alone and that life is in some way self-determining — the
research into complex adaptive matter says that life is the consequence
of molecular interactions.

"If we can discover organizing principles in biology other than evolution,
it means we will be able to make living systems in the laboratory," Dr.
Pines said. "We can understand how life began."

When Kandel, Schwartz and Jessell's *Principles of Neural Science*,
third edition, the best and most adopted handbook in the field, is opened
at
pp.209, a quotation from Bertil Hille appears:

"Electricity is used to gate channels and channels are used to make
electricity. However, the nervous system is not primarily an electrical
device. Most excitable cells ultimately translate their electrical
excitation into another form of activity. As a broad generalization,
excitable cells translate their electricity into action by Ca2+ fluxes
modulated by voltage-sensitive Ca2+ channels...(that) serve as the only
link to transduce depolarization into all the nonelectrical activities
controlled by excitation".

So we can see that at one level of organization the brain IS a quantum
system. Recently evidence has emerged about how this quantum system
works. For example, one of the proteins activated by Ca2+ entrance through
the
neuron membrane (by the NMDA channel) is calmodulin (CaM). A recent
study by Wilson and Brunger (Journal of Molecular Biology, 2000, 301, pp.
1237-1265) revealed that:

"Calmodulin...can bind specifically to over 100 protein targets in
response to a Ca2+ signal. Ca2+-CaM requires a considerable degree of structural
plasticity to accomplish this physiological role...the evidence for
disorder at every accessible length-scale in Ca2+-CaM suggests that the
protein
occupies a large number of hierarchically arranged conformational
substrates in the crystalline environment and may sample a quasi-continuous
spectrum of conformations in solution. Therefore, we propose that the functionally
distinct forms of CaM are less structurally distinct than previously
believed, and that the different activities of CaM in response to Ca2+
may result primarily from Ca2+-mediated alterations in the dynamics of
the
protein".

Are "Ca2+-mediated alterations" processes explained by classical
physics? Of course not. Little is known about this kind of "mesoscopic"
process, as
was made clear in an excellent interview by S. Blakeslee with scientists
fromthe new Institute for Complex Adaptive Matter (ICAM), at Los Alamos
Lab., UC/Berkeley - see http://www.nytimes.com/2001/04/24/health/24LIFE.html

Many molecular biologists, who are presumed to study interactions at
this level, limit themselves to the old lock-and-key metaphor when referring
to molecular binding (effector-protein, protein-substrate and/or
protein-protein), and on the other hand physicists have not frequently
focused on this kind of problem. The exception includes a minority of
inspired physicists who have studied quantum computation in biological
media.

I'm publishing a review paper with two Brazilian colleagues where we
associate conscious processing with quantum computation and
communication based on intra-cellular proteins which have a central role
in signal
transduction pathways and have been experimentally well related to
cognitive processing (e.g., proteins recently proved to have a central
role in
the formation of long-term-memories, as calmodulin-sensitive protein kinase
II - see "Alpha-CaMKII-dependent plasticity in the cortex is required for
permanent memory", Frankland, O'Brien, Ohno, Kirkwood & Silva, Nature,
17 May 2001, Vol. 411 No. 6835, pp. 223 - 398).

The reference of our paper is:
A. Freitas da Rocha, A. Pereira Jr., F.A. B. Coutinho (2001)
N-methyl-d-aspartate channel and consciousness: from signal coincidence
detection to quantum computing. Progress in Neurobiology, Vol. 64
Issue 6, Aug-2001, pp. 555 - 573.
The paper can already be obtained from http://www.neuroscion.com/This is a site I reccomend for everyone interested in neuroscience.
Registering for a free trial gives "credits" that can be used to
"purchase" this and other papers from several journals.

Best Regards to all,

From the time of Dionysius to
the time of Plato, the cultures of the Mediterranean consented to the doctrine
that claimed the existence of an order of ultimate reality which lies beyond
apparent reality. This "paranormal" reality was accessible to the consciousness
only when the "normal" routines of mental data processing were dislocated.
It was Plato's pupil Aristotle who changed his teacher's game, separating
physics from metaphysics. The philosophical temper of our present civilization,
being scientifically and technically oriented, is basically Aristotelian.

No such rational figure as Aristotle
arose in the Orient to a position of equal eminence. Because of this and
other reasons, Indian anatomists and zoologists, who where no doubt just
as curious as the Greeks about the origins of life, and as skilled in dissection,
did not feel compelled to set their disciplines up in opposition to metaphysics.
Physical and metaphysical philosophy remained joined like Siamese twins.
As a result, the discipline which became medicine in the West evolved into
a system known as Kundalini Yoga in the Hindu culture.

In Western terms, Kundalini
Yoga can be best understood as a biological statement contained within
the language of the poetic metaphor. The system makes the attempt of joining
the seeming disparate entities of body and mind. It is a very complicated
doctrine; in oversimplified terms, the system encourages the practitioner
to progress through the control of a number of stages, called Chakras or
mind-body coordination. A sixth, associated with clairvoyance and telepathy,
is called the Ajna.

The physiological site of this
sixth Chakra, the Ajna, is located in the center of the forehead. It is
symbolized by an eye - the so-called third eye, the inner eye, or the eye
of the mind. When this eye is opened, a new and completely different dimension
of reality is revealed to the practitioner of yoga. Western scholars when
they first encountered this literature, took the third eye to be an appropriately
poetic metaphor and nothing else.

It was not until the middle
of the nineteenth century, as the subcontinent of Australia and its surrounding
territory came to be explored, that a flurry of interest centered upon
a lizard native to the area, the tuatara (Sphenodon punctatum).
This animal possessed, in addition to two perfectly ordinary eyes located
on either side of its head, a third eye buried in the skull which was revealed
through an aperture in the bone, covered by a transparent membrane, and
surrounded by a rosette of scales. It was unmistakably a third eye but
upon dissection it proved to be non-functional.

Though this eye still possessed
the structure of a lens and a retina, these were found to be no longer
in good working order: also lacking were the appropriate neural connections
to the brain. The presence of this eye in the tuatara still posses a puzzle
to present-day evolutionists, for almost all vertebrates possess a homologous
structure in the center of their skull. It is present in many fish, all
reptiles, birds, and mammals (including man). This structure is known in
literature today as the pineal gland.

The gland is shaped like a tine
pine cone situated deep in the middle of the brain between the two hemispheres.
Studies then began to determine whether this organ was a true functioning
gland or merely a vestigial sight organ, a relic from our reptilian past.
In 1959 Dr. Aaron Lerner and his associates at Yale University found that
meletonin (1), a hormone manufactured by the pineal gland, was created
through the action of certain enzymes on a precursor chemical which must
pre-exist in the pineal in order for it to be transformed into melatonin.
This precursor chemical turned out to be serotonin (2).

It was E.J. Gaddum, a professor
of pharmacology at the University of Edinburgh, who was the first to note
a connection between serotonin and mental states of being. In a paper published
in 1953, he pointed out the fact that LSD-25 was a potent antagonist to
serotonin. Serotonin is not an unusual chemical in nature; it is found
in many places - some of them odd, like the salivary glands of octopuses,
others ordinary; it abounds in plants such as bananas, figs, and plums.
What then is its function in the human brain?

The task of exploring the role
played by melatonin, and its precursor serotonin, was undertaken by a biochemist,
Julius Axelrod. He found that melatonin suppressed physiological sexuality
in mammals. If test animals were stimulated to manufacture excessive amounts
of melatonin, their gonads and ovaries tended to become reduced in size,
to shrink, to atrophy. The estrous or fertility cycle in females could
likewise be altered experimentally by doses of melatonin.

Now two most curious functions
had been attributed to the pineal gland, the third eye of the mind:

(1) It has now been established
that this organ produced a chemical which had, indirectly at least, been
associated with psychedelic states. The chemical substance melanin
is the pigment which darkens skin color. It is located in specialized cells
scattered through the topmost layer of skin. Melatonin was found to be
the substance responsible for causing the contraction of melanin-producing
cells.

(2) It also produced a chemical
which suppressed functional sexuality. Serotonin is of the same chemical
series of indole alkaloids which include psychedelic drugs such as LSD-25,
psilocybin, D.M.T. and bufotenine. The hormone serotonin is also known
as 5-hydroxtryptamine.

The literature of religious
mysticism in all ages and all societies has viewed the mystical passion
of ecstasy as being somehow antagonistic to, or in competition with, carnal
passion.

Axelrod and his co-workers also
discovered another incredible fact: the pineal gland produces its chemical
according to a regular oscillating beat, the basis of this beat being the
so-called circadian rhythm. They found that the pineal responded somehow
to light conditions, that by altering light conditions they could extend,
contract, or even stabilize the chemical production rhythms of the pineal.

The fact that the pineal responds
to light, even if this response is indirect via the central nervous system,
has some fascinating and far-reaching conceptual applications. There are
many behavioral changes which overtake animals as the seasons change, and
which can be produced out of season in the laboratory by simulating the
appropriate span of artificial daylight. Do such seasonal changes in mood
and behavior persist in humans?

The great religious holy days
of all faiths tend to cluster around the times of the solstices and equinoxes.
Is it possible that the human pineal gland responds to these alterations
in length of daylight? Changing the balance of neurohumors in the brain
may perhaps effect a greater incidence of psychedelic states in certain
susceptible individuals just at these crucial times. This possibility provides
an entirely new potential dimension to our secular understanding of the
religious experience.

The pineal gland has thus been
referred to as a kind of biological clock, one which acts as a kind of
coupling system; perhaps maintaining phase relations within a multi-oscillator
system; a phase coordinator for multiple bio-rhythms. The pineal is a "cosmic
eye;" it is aware of celestial rhythm. It "tunes" our biochemistry to those
subtle rhythms not observed by the normal eye, like seasonal and lunar
changes rather than daily ones. Serotonin can be seen as the "intensity
knob" of the brain. As the level of serotonin increases, so does the level
of activation of the cortex.

Strong suspicion has fallen
now on serotonin as being one of the principle agents of the psychedelic
experience. Studies now reveal that LSD-25 strikes like a chemical guerrilla,
entering into receptor granules in the brain cells swiftly, and then leaving
after a very short time, perhaps ten to twenty minutes (in animals). When
the bulk of LSD-25 has left the receptor granules, it is replaced by what
seems to be excessive, or super-normal amounts of serotonin. The LSD-25
creates what is called a "bouncing effect," like a spring pushed too tight.
When the LSD-25 leaves the system, the serotonin springs back and overcompensates.

For most of us, most of the
time, our world is a Darwinian environment. We must manipulate ourselves
within it, or attempt to manipulate it in order to survive. These survival
needs tend to color our appreciation of this world, and we are continually
making judgments about it. Some of these judgments are based on prior personal
experience, others are provide by the culture. This "recognition system"
is one of the elements disrupted by the psychedelic state.

The principle question concerning
psychedelic states remains: How much disruption can the system tolerate?
The problem of how to maintain a certain madness while at the same time
functioning at peak efficiency has now captured the attention of many psychiatrists.
There seems to be a point at which Edgar Allen Poe's "creative madness"
becomes degenerative, impeding function rather than stimulating it.

In light of this analysis, a
shaman can be seen to be uncoupling his internal bio-sensor from the universal
inputs. He gets "drift" where he is rushed toward new signal-to-noise ratios.
The particular rituals are set up to disconnect the shaman from his social
and cosmic environment. This is done through the ritual use of hallucinogens;
they de-synchronize his internal rhythms. This de-synchronization produces
more noise in his awareness. It also expands that awareness. The rituals
are so designed as to contain elements which focus or tune that "noise"
and direct the expanded awareness.

Man is unique by virtue of being
possessed by intuitions concerning the scope of the mysterious universe
he inhabits. He has devised for himself all manner of instruments to prove
the nature of this universe. The beginnings of scientific understanding
of shamanistic ritual and the function of the third eye provide man with
powerful new techniques for exploration. This will allow him to penetrate
the vast interior spaces where the history of millions of years of memories
lies entangled among the roots of the primordial self.

INTRODUCTION TO
TRANSCRANIAL MAGNETIC STIMULATION

SUMMARY:Brain stimulation with
TMS is achieved from the outside of the head using pulses of electromagnetic
field that induce an electric field in the brain. TMS has numerous applications
in the study, diagnosis and therapy of the brain. TMS can either excite
the cortex or disturb its function. The concurrent use of TMS and
high-resolution EEG shows that the combination is effective for mapping
the functional connections in the brain. Under EEG, a TMS pulse to
the motor area of the left hemisphere is seen to move to the opposite hemisphere,
suggesting a callosal connection between the two active areas. The
neuronal response to magnetic stimulation reveals cortical reactivity and
connectivity.

TMS holds special promise as a tool to study localization of function,
connectivity of brain regions, and pathophysiology of neuropsychiatric
disorders. It may also have potential as a therapeutic intervention.
TMS has been referred to as "electrodeless" electrical stimulation, to
emphasize that the magnetic field acts as the medium between electricity
in the coil and induced electrical currents in the brain. The proximity
of the brain to the time-varying magnetic field results in current flow
in neural tissues.

Neuronal depolarization can also be produced by electrical stimulation,
with electrodes placed on the scalp (referred to as transcranial electric
stimulation). Electroconvulsive therapy (ECT) is an example of this. Importantly,
unlike electrical stimulation, where the skull acts as a massive resistor,
magnetic fields are not deflected or attenuated by intervening tissue.
This means that TMS can be more focal than electric stimulation. Furthermore,
for electrical stimulation to achieve sufficient current density in brain
to result in neuronal depolarization, pain receptors in the scalp must
be stimulated.

A striking effect of TMS occurs when one places the coil on the scalp over
primary motor cortex. A single TMS pulse of sufficient intensity causes
involuntary movement. The magnetic field intensity needed to produce motor
movement varies considerably across individuals, and is known as the motor
threshold. Placing the coil over different areas of the motor cortex
causes contralateral movement in different distal muscles, corresponding
to the well-known homunculus. Transcranial magnetic stimulation can be
used to map the representation of body parts in the motor cortex on an
individual basis. Subjectively, this stimulation feels much like
a tendon reflex movement.

Thus, a TMS pulse produces a powerful but brief magnetic field that passes
through the skin, soft tissue, and skull, and induces electrical current
in neurons, causing depolarization that then has behavioral effects (body
movement). The TMS magnetic field declines logarithmically with distance
from the coil. This limits the area of depolarization with current technology
to a depth of about 2 cm below the brain's surface.

Single TMS over motor cortex can produce simple movements. Over primary
visual cortex, TMS can produce the perception of flashes of light or phosphenes.
To date, these are the "positive" behavioral effects of TMS. Other immediate
behavioral effects are generally disruptive. Interference with information
processing and behavior is especially likely when TMS pulses are delivered
rapidly and repetitively. Repeated rhythmic TMS is called repetitive TMS
(rTMS). If the stimulation occurs faster than once per second (1 Hz) it
is referred to as fast rTMS.

A key distinction between TMS research and work on the behavioral effects
of exposure to magnetic fields is that TMS effects occur at or near intensities
sufficient to produce cortical neuron depolarization. The capacity to noninvasively
excite or inhibit focal cortical areas represents a remarkable advance
for neuroscience research. As an interventional probe in neuropsychiatric
disorders, rTMS has the potential of taking functional imaging one step
further by elucidating causal relationships. Experimental treatment
of depression with TMS showed evidence that modulation of precrontal function
is linked to the efficacy of ECT. Studies combining SSRIs with rTMS
showed the rTMS group with a faster antidepressant response. It is
unknown whether the effect is region or frequency dependent.
TMS is relatively benign. Repetetive TMS does not involve anesthesia
administration or seizure induction and has no ovious sequelae as does
ECT.

There is evidence that rTMS can modulate mood systems in normal volunteers.
Three studies found that rTMS over the left DLPFC transiently induced a
mild increase in self-rated sadness, whereas right DLPFC rTMS produced
a mild increase in self-rated happiness as early as 20 minutes or as late
as 5 to 8 hours poststimulation. As described, the mood effects of
rTMS in patients with major depression may have an opposite laterality
to those seen in normal volunteers. There has yet to be an investigation
using TMS to probe the anatomy subserving the perception or expression
of emotion

Transcranial magnetic stimulation carries the vision of tailoring the site
and nature of stimulation to individual needs. It is uncertain whether
this vision will be realized and whether a treatment role for rTMS will
emerge. At the practical level, rTMS research is not supported with the
resources devoted to pharmaceutical development. Given the large parameter
space, it is difficult to see how rTMS treatment applications can be optimized
without considerable basic research extending from cell culture preparations
through whole animal models, including humans.

Some preliminary studies suggest that rTMS effects on cortical excitability
may depend on the frequency of stimulation. Manipulations of frequency
and intensity may produce distinct patterns of facilitation (fast rTMS)
and inhibition (slow rTMS) of motor responses with distinct time courses.
These effects may last beyond the duration of the rTMS trains with enduring
effects on spontaneous neuronal firing rates.

To use TMS optimally, it is important to know how TMS is acting in the
brain. Does TMS mimic normal brain physiology, or is it supraphysiologically
depolarizing and activating different cell groups (excitatory, inhibitory,
local, or remote) in a large region? Understanding of TMS mechanisms is
being advanced through studies in animal models and by combining TMS with
functional neuroimaging.

Neuroimaging studies have shown that TMS is biologically active, both locally
in tissue under the coil and at remote sites, presumably through transsynaptic
connections. Several studies have shown that the different parameters used
in rTMS (location, intensity, frequency) affect the extent and type of
neurophysiological alterations. Thus, there is considerable promise that
functional imaging research will help elucidate basic TMS effects and the
roles that different TMS parameters exert in modulating these effects.
Theoretically, this may advance clinical research, particularly if combinations
of location, intensity, and frequency are found to have divergent effects
on neuronal activity. Transcranial magnetic stimulation imaging studies
can be divided into 2 main categories: (1) using imaging to guide TMS coil
placement and understand the spatial distribution of TMS magnetic fields
in the brain, and (2) using imaging to measure TMS effects on neuronal
activity.

Bohning et al demonstrated that an MRI scanner can be used to display the
TMS magnetic field (producing a phase map; Figure 2). This work
confirmed that the TMS field is not altered appreciably by head geometry.
Further, by combining several TMS coils with different relative orientations,
this technique can measure in 3 dimensions the capacity to focus and combine
magnetic fields. Ultimately, TMS coil arrays combined with MRI may target
deep brain structures. Owing to seizure risk at moderate intensity,
fast rTMS can only be given in short pulse trains (1-8 seconds) with relatively
long intervals between trains (20 seconds).

A major hypothesis in the TMS field has been that fast rTMS results in
excitatory physiological changes, while slow rTMS has inhibitory effects.
To date, imaging studies have yielded inconsistent results regarding this
proposition. In fact, some slow rTMS imaging studies over motor or prefrontal
cortex have found decreased local and remote brain activity, while others
have found increases. Some imaging studies of fast rTMS have found
increased perfusion, but not all.

Transcranial magnetic stimulation is not pleasant, and stimulation at higher
intensities and frequencies is generally more painful. The pain experienced
during rTMS is likely related to the repetitive stimulation of peripheral
facial and scalp muscles, resulting in muscle tension headaches in a proportion
of subjects (approximately 5%-20% depending on the study). These headaches
respond to treatment with acetaminophen or aspirin. Magnetic stimulation
also produces a high-frequency noise artifact that can cause short-term
changes in hearing threshold. This is avoided when subjects and investigators
wear earplugs.

rTMS has resulted in seizures. The risk of seizure induction
is related to the parameters of stimulation, and no seizures have been
reported with single-pulse TMS or rTMS delivered at a slow frequency (<1
Hz). There is a growing understanding of the rTMS parameter combinations
(magnetic intensity, pulse frequency, train duration, and intertrain interval)
that result in spread of excitation, heralding impending seizure. Even
if therapeutic benefits are convincingly shown, the seizure risk may limit
the widespread and loosely supervised use of rTMS. In part for this reason,
the therapeutic potential of slow-frequency (<1 Hz) deserves
particular attention.

Gates et al performed histological examinations of the resected temporal
lobes of 2 patients with epilepsy who preoperatively received approximately
2000 stimulations over this tissue.[143] Lesions attributable to TMS were
not found. Magnetic resonance imaging scans done before and after 2 weeks
of rTMS in 30 depressed patients did not show change.

Both TMS and rTMS can disrupt cognition during the period of stimulation.
However, the safety concerns are about alterations in cognitive function
beyond the period of stimulation. The limited investigation of short-term
neuropsychological effects of TMS has not demonstrated significant changes.[39]
Little information is available about long-term effects. The technique
has been in use for more than a decade without reports of long-term adverse
consequences. The rate of cancer is not increased in individuals with prolonged
exposure to high-intensity magnetic fields, such as MRI technicians.
However, TMS involves extremely brief, focal exposure to high-intensity
magnetic fields and thus safety information from MRI technicians, or even
people who live near power lines (lengthy exposure to low-intensity magnetic
fields) may not be germane.

Controlled trials across a variety of neuropsychiatric conditions are underway,
yet safety information is limited. Reassuringly, single-pulse and other
TMS measures of cortical excitability are believed to be devoid of significant
safety concerns. However, rTMS has shown potential to ameliorate neuropsychiatric
symptoms. The potential for adverse cognitive effects must be considered
precisely because it is hypothesized that rTMS is a sufficiently powerful
modulator of regional functional activity to have therapeutic properties.
More comprehensive neuropsychological evaluations of the short- and long-term
effects of rTMS are needed.

ECT presents the one situation in humans in which seizures are provoked
for therapeutic purposes. A reliable method of seizure induction with TMS
may have important advantages over traditional ECT by offering better control
over the intensity and spatial distribution of current density in the brain.
Developing a TMS form of convulsive therapy is largely an issue of technological
advances in stimulator output and coil design. Such a development may also
foster better understanding of the safety of nonconvulsive uses of rTMS.

CONCLUSIONS

During the next several years, it will become clearer whether rTMS has
a role in the treatment of psychiatric disorders. To date, trials in depression
have focused on demonstrating antidepressant properties and have not demonstrated
clinical utility. We need to know a good deal more about the patients who
benefit from rTMS, the optimal form of treatment delivery, the magnitude
and persistence of therapeutic effects, the capability of sustaining improvement
with rTMS or other modalities, and the risks of treatment. It is still
too early to know whether we are at the threshold of a new era in physical
treatments and noninvasive regional brain modulation. Regardless of its
potential therapeutic role, the capacity of rTMS to noninvasively and focally
alter functional brain activity should lead to important advances in our
understanding of brain-behavior relationships and the pathophysiology of
neuropsychiatric disorders.

1 Introduction

The use of non-invasive neuroimaging has increased explosively in recent
years. Details of the functioning of the human brain are revealed by measuring
electromagnetic fields outside the head or metabolic and hemodynamic changes
using electroencephalography (EEG), magnetoencephalography (MEG), positron
emission tomography (PET), near-infrared spectroscopy (NIRS) or functional
magnetic resonance imaging (fMRI). This thesis deals with transcranial
magnetic brain stimulation (TMS), which is a direct way of manipulating
and interfering with the function of the cortex, thus complementing conventional
neuroimaging.

Brain stimulation with TMS is achieved from the outside of the head
using pulses of electromagnetic field that induce an electric field in
the brain. TMS has numerous applications in the study, diagnosis and therapy
of the brain. TMS can either excite the cortex or disturb its function.
The observed excitatory effects are normally muscle twitches or phosphenes,
whereas in the "lesion" mode TMS can transiently suppress perception or
interfere with task performance.

The aim of this thesis was to develop physical understanding of magnetic
stimulation and to build models that could provide new insights for utilising
the technique. For this purpose, two principal issues had to be addressed:
1) macroscopic electromagnetic fields in the tissue, for which models are
developed in Publications I-III, and 2) understanding
of the neuronal responses, considered in Publications IV and V. Then, the
models developed were used as a basis for engineering modifications that
would increase the utility of TMS, the emphasis being on the optimisation
of the stimulating coils (Publication VI) and on the use of multiple coils
in a whole-scalp array (Publication VII). Publication VIII presents the
concurrent use of TMS and high-resolution EEG, showing that the combination
is effective for mapping the functional connections in the brain.

The models and procedures were developed in parallel with the design
and construction of TMS instrumentation for computer-assisted stimulation.

2.1 Basic principles

Neurones can be excited by externally applied time-varying electromagnetic
fields. In TMS, excitation is achieved by driving intense pulses of current
I(t)
through a coil located above the head. The source of activation is the
electric field E induced in the tissue, obtained from Faraday’s
law:

where B is the magnetic field produced by the coil, given by
the Biot-Savart law:

The integration is performed with the vector dl along
the coil windings C and m0=
4p´ 10-7
H/m is the permeability of free space.

The pulses of current are generated with a circuit containing a discharge
capacitor connected with the coil in series by a thyristor. With the capacitor
first charged to 2-3 kV, the gating of the thyristor
into the conducting state will cause the discharging of the capacitor through
the coil. The resulting current waveform is typically a damped sinusoidal
pulse that lasts about 300 ms and has a peak
value of 5-10 kA. The electrical principles
have been outlined, e.g., by Jalinous [72,73].

Figure 1 summarises the chain of events in TMS. The induced E
is strongest near the coil and typically stimulates a cortical area of
a few centimetres in diameter. TMS pulses cause coherent firing of neurones
in the stimulated area as well as changed firing due to synaptic input.
At microscopic level, E affects the neurones’ transmembrane voltage
and thereby the voltage-sensitive ion channels. Brain imaging tools can
be used to detect the associated electrical currents and changes in blood
flow of metabolism. In motor-cortex stimulation, peripheral effects can
be observed as muscle activity with surface electromyography (EMG). Moreover,
there may be behavioural changes, for instance, impaired task performance.

Stimulation of the exposed human cerebral cortex with electrical currents
was first described by Bartholow in 1874 [11]; the currents elicited movements
of the opposite side of the body. Electrical brain stimulation is today
possible non-invasively using scalp electrodes [96]. However, transcranial
electrical stimulation (TCES) is very painful and hence of limited value.

The first experiments with magnetic stimulation were conducted by d’Arsonval
in 1896 [36]. He reported "phosphenes and vertigo, and in some persons,
syncope," when the subject's head was placed inside an induction coil.
Later, many scientists reported the phenomenon of magnetophosphenes, that
is, visual sensations caused by the stimulation of the retina due to changing
magnetic fields [10,15,41,92,155,159].

Magnetic nerve stimulation was accomplished only several decades
later, first in the frog by Kolin et al. [79] in 1959 and then in
the human peripheral nerve by Bickford and Fremming [17] in 1965. The latter
authors used an oscillatory magnetic field that lasted 40 ms. The resulting
long-lasting activation interval made it impossible to record nerve or
muscle action potentials, and the work was not pursued further. In the
following years, the technique was investigated only occasionally [68,87,118].

In 1982, Polson, Barker and Freeston [128] described a prototype magnetic
stimulator for peripheral nerve stimulation. They used 2-ms-duration pulses
and recorded, for the first time, motor-evoked potentials (MEPs) obtained
by median nerve magnetic stimulation. In present-day devices, the pulse
duration is typically shorter.

In 1985, the Sheffield group achieved successful transcranial magnetic
stimulation [9] and made the first clinical examinations [6]. TMS proved
valuable for probing the motor pathways: in healthy subjects, stimulation
over the motor cortex causes twitches in hand muscles in about 25 ms, while
many neurological conditions manifest slower conduction. Another important
characteristic of TMS is that it is painless, the subject usually feeling
only a not uncomfortable sensation of scalp being pinched. The encouraging
results led into commercialisation of TMS by Novametrix Ltd. (predecessor
of Magstim Company).

Since 1985, magnetic stimulator technology has remained mostly unchanged.
Whereas early research used circular coils, today devices are usually equipped
also with an 8-shaped, or figure-of-eight coil proposed by Ueno [157].
The 8-shaped coil induces a more concentrated electric field than the circular
coil, resulting in better control of the spatial extent of the excitation.
Another important development is repetitive TMS (rTMS) capable of delivering
trains of stimuli at 1-50 Hz. rTMS was first
produced by Cadwell Laboratories in 1988 and is today one of the most quickly
growing areas of TMS research.

Magnetic therapy or rapid
transcranial magnetic stimulation (rTMS) has been proposed as a possible
new treatment for severe depression. This treatment involves the passage
of magnetic waves through the skull using a special machine. Several treatments
are required. Unlike electro-convulsive therapy, no anesthesia is necessary.
There are no obvious major side effects from treatment.

From a medical perspective, the use
of rTMS is based on studies which suggest that the left prefrontal lobe
of the brain is pathophysiologically linked to depression. When research
was conducted using non depressed volunteers, it showed that rTMS to prefrontal
structure in the brain had a lateralised effect on mood. When preliminary
studies were conducted using volunteers with depression a beneficial effect
of rTMS on depression was suggested.

This treatment is in its very early
stages and the limited research findings suggest that there may be improvement
in selected patients. To date, the treatment has only been used in patients
with very severe depression who have failed all other treatments. Therefore,
at this point in time, magnetic therapy is mostly applied to patients who
have severely resistant depression. As the role and effectiveness of this
treatment become better established, its possible use across a broad range
of depressive illnesses can be better evaluated. At that time, its role
in the treatment of major depression as compared with anti-depressants
and particularly electro-convulsive therapy can be further evaluated.

April 1999

Transcranial Magnetic Stimulation

Applications in Neuropsychiatry

Mark S. George, MD; Sarah H. Lisanby, MD; Harold A. Sackeim, PhD

In the 1990s, it is difficult to open a newspaper or watch television
and not find someone claiming that magnets promote healing. Rarely do these
claims stem from double-blind, peer-reviewed studies, making it difficult
to separate the wheat from the chaff. The current fads resemble those at
the end of the last century, when many were falsely touting the benefits
of direct electrical and weak magnetic stimulation. Yet in the midst of
this popular interest in magnetic therapy, a new neuroscience field has
developed that uses powerful magnetic fields to alter brain activity—transcranial
magnetic stimulation. This review examines the basic principles underlying
transcranial magnetic stimulation, and describes how it differs from electrical
stimulation or other uses of magnets. Initial studies in this field are
critically summarized, particularly as they pertain to the pathophysiology
and treatment of neuropsychiatric disorders. Transcranial magnetic stimulation
is a promising new research and, perhaps, therapeutic tool, but more work
remains before it can be fully integrated in psychiatry's diagnostic and
therapeutic armamentarium.

Arch Gen Psychiatry. 1999;56:300-311

Bioelectricity in Neurons

Misconceptions about neurobio-electrical energy

Many encyclopedias, dictionaries, and textbooks contain very clear statements
about the nature of
bio-electricity. They say this:

Bio-electricity is a type of energy.
Bio-Electric current is a flow of energy.

The above statements are wrong. Bio-electricity is not energy. Bio-electricity
and bio-electrical energy are two different things. It's not too difficult
to show that this is true. Below is a collection of simple facts which
demonstrate that bio-electricity, the stuff that flows within neural axons/dendrites,
is not a form of energy.

In a simple neuro-electric circuit, the bio-electricity flows in a circle.
No bio-electricity is ever gained or lost. On the other hand, the neuron
is a battery (replenished by ADP Na+/K+ pump) that creates bio-electrical
energy.

In a neuron, bio-electricity flows through the body and none is lost. Bio-electricity
enters the neuron through dendritic wires, and the same amount leaves through
the axonal wire. Yet the neuron uses up bio-electric energy: the
bio-electric energy flows into the neuron, and it does not come back out
again.

In a neuron, the bio-electricity (Na, K) moves back and forth across the
leaky membranes. In other words, the charged particles remain localized,
they simply oscillate back and forth across a local membrane. Ions do not
move forward at all (if they did, that would be a direct current or "DC.")
At the same time, the bio-electrical energy moves forward rapidly. Only
the bio-electricity "vibrates." The energy does not; the bio-energy flows
continuously forwards.

Ionic charges are not in and of themselves energy any more than the water
particles in the above energy wave.

The neuronal action potential therefore is a way of transmitting neuroelectrical
energy without transmitting the ionic particles of electricity (Na, K,
Ca, etc).

My above statements about bio-electricity would be accepted by most scientists
throughout history, including Ben Franklin, Michael Faraday, James C. Maxwell
and Robert Millikan. I'm using the word bio-electricity in the same manner
as they did: bio-electricity is the positive and negative "stuff" that's
found in electrons and protons. It is the "substance" that flows along
inside of the wires. These scientists would call this flow a "current of
bio-electricity." They'd say that any charged object has a "charge of bio-electricity,"
and that anions and cations are "particles of bio-electricity."

MORE TRUE STATEMENTS ABOUT "bio-electricity"

If we know the precise amount of bio-electricity flowing per second
through a wire (the Amperes,) this tells us nothing about the amount of
energy being delivered per second (the Watts.) A bio-electric current is
not a flow of energy.

In a bio-electric circuit, the flow of the bio-electricity is measured
in Coulombs per second (Amperes.) The flow of energy is measured in Joules
per second (Watts.) A Coulomb is not a Joule, and there is no way to convert
from Coulombs to Joules or from Amperes to Watts. A flow of bio-electricity
is not a flow of energy.

In a DC circuit, the bio-electricity within the wires flows exceedingly
slowly; on the order of inches per minute. At the same time, the electrical
energy flows at nearly the speed of light.

Bio-Electrical energy is bio-electromagnetism; it is a bio-electromagnetic
field. The particles of bio-electricity (anions/cations) flowing within
a wire have little resemblance to an electromagnetic field. They are matter.
Bio-electricity is not energy, instead it is a component of everyday matter.

In a neuro-electric circuit, bio-electrical energy does not flow
inside the axon. Instead it flows in the space surrounding the axons. Physics
books describe one method of measuring this flow: take the vector cross-product
of the E and M components of the electromagnetic field at all points in
a plane penetrated by the wires. We call this the Poynting Vector field.
Add these measurements together, and this tells us the total energy flow
(the Joules of energy that flow each second.) To discover the rate of energy
flow, don't look at the flowing electrons. The bio-electricity flow tells
us little. Instead look at the electromagnetic fields which surround the
wires.

In any bio-electric circuit, the smallest particle of electrical
energy is NOT the anion/cation, the electron or proton. The smallest particle
of energy is the unit quantum of electromagnetic energy: it is the bio-photon.
Bio-electricity is made of ions, while bio-electrical energy is made of
photons.

In the bio-electric neuronal ensemble, a certain amount of energy is lost
because it flies off into extra-cellular space. This is well understood:
electrical energy is electromagnetic waves, and unless the axons are somehow
shielded, (which they are with Schwann cells) they will act as 60Hz antennas.
Waves of 60Hz electrical energy will spread outwards into space rather
than following the wires.

A battery or generator is like your heart: it moves blood, but it does
not create blood. When a generator stops, or when the a metal circuit is
opened, all the electrons stop where they are, and the wires remain filled
with electric charges. But this isn't unexpected, because the wires were
full of vast quantities of charge in the first place.

Neuro-electric currents in axons are a flow of ions, but these ions are
not supplied by neurons themselves. They come from the both the intra and
extra cellular ions. These ions were already in the circuit before the
ATP-battery was connected. Batteries and generators do not create
these ions, they merely pump them, and the ions are like a pre-existing
fluid that is always found within all axons. In order to understand neuro-electric
circuits, we must imagine that all the axons are pre-filled with a sort
of "liquid electricity."

A bio-electric current is a FLOW OF CHARGE. A bio-electric current
is a flowing motion of charged particles, anions/cations. The words "Electric
Current" mean the same as "charge flow." Bio-electric current is
a very slow flow of charges. On the other hand, electric energy is made
of fields and it moves VERY rapidly. Neuro-electric energy moves at a different
speed than neuro-electric current, so obviously they are two different
things.

Neuro-electric energy is composed of electric and magnetic fields, and
it exists in the space surrounding the axons. Neuro-electric energy is
very similar to radio waves, but it is very low in frequency. Neuro-electric
CHARGE is very different than the energy. The charge-flow (current) is
a flowing motion usually of ions, and ions are material particles, not
energy particles.

And it's not always a flow of electrons: when electric current exists inside
an electrolyte (in batteries, salt water, the earth, or in your flesh)
it is a flow of charged atoms called ions, so there is no denying that
it is a flow of material. Current is a matter-flow, not an energy flow.

The energy in neuro-electric circuits is not carried by individual ions,
it is carried by the circuit as a whole.

Here's one way to clarify the muddled concepts: if electric current is
like a flow of air inside a pipe, then electrical energy is like sound
waves in the pipe, and electrons are like the air molecules. Sound can
travel through a pipe if the pipe is full of air molecules, and electrical
energy can flow along a wire because the wire is full of movable charges.
Sound moves much faster than wind, correct? And electrical energy moves
much faster than electric current for much the same reason.

In any neuro-electric circuit, the smallest particle of electrical energy
is NOT the anion/cation or electron/proton. The smallest particle of energy
is the unit quantum of electromagnetic energy: it is the photon. Neuro-electricity
and its currents are made of ions, while electrical energy is made of photons.

Just as in modern electronics, a radio for instance, information is not
carried in the movement of electrons in the wires and antennas but in the
modulations of electro-magnetic waves, neural information is not
carried by ionic currents, action potentials, but in the modulation of
bio-electromagnetic energy - ie. bio-photons.

A photon is not simply a quantum of visible light, but a quantum of the
entire electromagnetic spectrum of energy. Since neurological systems
produce electromagnetic energy, bio-photons should not be a surprise.